LAUSR

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder that affects approximately 45% of male and 16% of female carriers of a fragile X mental retardation 1 (FMR1) gene premutation over the age of 50 years [1]. Premutations of 55 to 200 CGG repeats of the FMR1 gene translate into increased FMR1mRNA, inducing a toxic gain of function and/or translation of CGG repeats into a polyglycine-containing protein, FMRpolyG [1, 2]. Notably, almost all premutation carriers with neurological symptoms present with FXTAS and/or have inclusions on autopsy [3]. Such pathology includes eosinophilic ubiquitin-positive intranuclear inclusions, which contain FMR1 mRNA and numerous proteins in neurons and astrocytes [4–6]. Defining clinical features of FXTAS include progressive action tremor, gait ataxia, impaired executive function and memory deficits, peripheral neuropathy, and parkinsonism [1]. Associated variable features include cognitive impairment and dementia; psychiatric symptoms, such as depression; and dysautonomia [7–9]. Radiologically, FXTAS is characterized by progressive global brain atrophy and white matter disease of both the cerebellum and cerebrum [10, 11]. Importantly, cerebellar and brainstem atrophy and ventricular enlargement are detectable even before the onset of tremor or ataxia [12, 13]. Currently, no specific treatment for FXTAS can slow the progression of neurodegeneration, though symptomatic treatments exist for some of the symptoms, such as tremor [14]. Only one previous controlled trial has been performed in individuals with FXTAS, a memantine trial lasting 1 year, but this treatment did not improve tremor, ataxia, or executive function [15, 16]. The study in this issue of Neurotherapeutics byWang et al. [17] assessed whether allopregnanolone, a neurosteroid that promotes regeneration and repair, can improve clinical symptoms, brain activity, and magnetic resonance imaging (MRI) measurements in patients with FXTAS. In this preliminary, 3month, open-label, uncontrolled trial, 6 men with FXTAS underwent weekly intravenous infusions of allopregnanolone (26 mg over 30 min) for 12 weeks. The Richmond Agitation Sedation Scale was administered before, during, and after each infusion. Plasma allopregnanolone levels were determined by liquid chromatography–tandem mass spectrometry in 1 subject from blood samples drawn at intervals during and after a 6-mg infusion from the opposite arm of that receiving the intravenous infusion. All patients completed baseline and follow-up clinical examinations and neuropsychological assessments. Functional outcomes included quantitative measurements of tremor and ataxia, as well as neuropsychological evaluations. In line with recent recommendations in the fragile X field [18], a wide range of neuropsychological, behavioral, neurophysiological, and structural imaging studies were applied. For example, learning and memory was measured via the California Verbal Learning Test 2, whereas working memory was assessed using Wechsler Memory Scale-IV. Measuring of brain activity consisted of event-related potential (ERP) N400 word repetition effect during a semantic memory processing task. Structural MRI outcomes comprised volumes of the hippocampus, amygdala, and fluid-attenuated inversion recovery hyperintensities, andmicrostructural integrity of the corpus callosum. It is noteworthy that before the treatment, the patients exhibited impairment in executive function, verbal fluency and learning, and had progressive deterioration of all MRI measurements. * Dejan B. Budimirovic [email protected]